Abstract An exciting and promising new avenue for cancer treatment is the inhibition of immune evasion ? the employment by tumors of various strategies to suppress the host immune system?s ability to recognize and destroy cancer cells. Immunotherapies, including monoclonal antibodies, transplanted stem cells and engineered T-cells, vaccines, cytokines, and T-cell checkpoint blockers have shown efficacy against hematologic and solid tumors. Owing to the complexity of immune evasion, however, combination protocols will likely be needed for optimal therapeutic management. Side effects associated with current immunotherapies, including severe autoimmune disease, also support development of alternative immuno-oncology agents. Thus, there is much interest among biotech and pharmaceutical organizations and academic laboratories to find small molecules that promote anti-tumor immunity. A promising new target is Cbl-b, a RING finger E3-ubiquitin ligase expressed primarily in immune cells and critical to immune suppression in the form of T-Cell anergy induced by TGF-? and regulatory T cells (Treg). Cbl-b ubiquitylates the p85 subunit of PI3K, disrupting its recruitment to CD28 in T cells, and has an inhibitory role in regulating NK cell functions via TAM receptor kinases. Cbl-b-/- mice reject various implanted tumors and significantly delay outgrowth of spontaneous tumors; either knocking out Cbl-b or inhibiting TAM kinases leads to NK cell mediated rejection of metastases. Antitumor activity of Cbl-b-/- mice is attributed to hyperactivated CD8+ T cells and NK cells. Thus, Cbl-b is a well-validated immuno-oncology target and Cbl-b inhibitors are expected to decrease p85 ubiquitylation and TAM receptor kinases, promoting T and NK cell activation. In an HTS campaign using a homogenous TR-FRET based Tyro3 substrate ubiquitylation assay, Progenra discovered novel selective Cbl-b inhibitors and demonstrated efficacy in various cellular models including primary T and NK cells. It is proposed here to conduct hit to lead optimization of Cbl-b inhibitors and evaluate them in biochemical, cellular and genetic models of T- and NK-cell activation. In particular, Cbl-b inhibitors are expected to decrease ubiquitylation of substrates Tyro3 and p85, increase cytokine production (e.g.,,IL-2 and IFN?), and activate T and NK cells. Selective Cbl-b inhibitors demonstrating cellular and in vivo proof of concept will enter pre-clinical development in Phase II (chemical optimization, ADME, in vivo efficacy) as clinical candidates for novel immuno-oncology therapies.